Huntington's disease is an autosomal dominant, neurodegenerative disorder caused by an expansion in the polyglutamine (CAG) stretch located within exon 1 of the huntingtin gene. Although huntingtin is expressed ubiquitously, primarily two cell types die - the medium spiny neurons of the striatum and pyramidal neurons in layers III, V, and VI of the cortex. A number of mouse models have been generated to study the mechanisms of mutant huntingtin pathology, but none have been successful at producing a model that accurately and regulatably induces the characteristic pattern of neurodegeneration in HD. Therefore, the first Aim of these experiments is to generate a regulatable mouse model of HD using BAC technology and the lac operator/repressor system. In Aim 2, tissue-specific repressor mice will be generated which, in combination with the regulatable HD mouse model, will be used to test the hypothesis that mutant huntingtin acts cell autonomously in the cell types most affected by HD. The results obtained from these experiments will provide better clarification of how mutant htt exerts its toxic effects, and enable the field to focus future efforts on the primary cell types affected by HD.